Project Summary/Abstract Genetic loss or acquisition of missense mutations within the phosphatase and tensin homolog (PTEN) gene is a frequent event in glioblastoma multiforme (GBM). Loss of PTEN activity leads to a robust activation of PI3K signaling due to its established role as a lipid phosphatase but also to an activation of the MAPK pathway. Missense mutations within PTEN that retain phosphatase catalytic activity are common in GBM and we demonstrate their capacity to drive gliomagenesis in vitro. The molecular mechanisms by which these mutations abrogate PTEN's tumor suppressive function are unknown and represent a crucial area of research in cancer. We hypothesize that phosphatase activity-retaining missense mutations are not synonymous to complete loss of PTEN or phosphatase activity dead missense mutants in their mechanisms of tumor suppression and represent distinct categories of PTEN driven cancers that will respond differently to PI3K- and MEK-centric treatment regimens. On this basis, we propose to 1) develop new PTEN genetically engineered mouse models of missense mutants and utilize these models to optimize targeted therapies against PI3K and MEK, and 2) create isogenic PTEN missense mutant human GBM PDX lines to uncover new PI3K and MEK inhibition strategies. The overall goal of the proposed research is to deliver on an effective translational use of genetically cutting edge models of GBM that accurately recapitulate human disease to direct research toward the development of new treatments.